This application investigates the hypothesis that energy balance and body fuel stores in the form of adipose tissue are subject to homeostatic regulation. The key elements of this regulatory system include hormonal signals such as leptid (the adipocyte hormone encoded by the ob gene) and adrenal glucocorticoids, and hypothalamic peptides such as neuropeptide Y (NPY, a peptide that stimulates food intake and promote weight gain), and corticotrophin releasing hormone (CFH, which promotes weight loss by reducing caloric intake and increasing expenditure). Leptin is proposed to be a negative feedback signal secreted in proportion to the level of adipose sores that acts in the brain to promote weight loss by the combined effect of inhibiting NPY and stimulating CRH signaling pathways in the hypothalamus. Glucocorticoids are proposed to modify this leptin effect by opposing its hypothalmic actions. The Specific Aims of this proposal seek to test this model of neuroendocrine control of energy homeostasis by determining 1) the compensatory mechanisms(s) by which mice with genetic NPY deficiency maintain normal energy balance, 2) whether the relative contributions of NYP and CRH as mediators of leptin action can change as a result of weight loss or genetic obesity, 3) if NPY acts directly in the brain to inhibit CRH biosynthesis, and 4) whether CRH signaling can influence food intake and energy balance independently of its effects on the hypothalamic- pituitary-adrenal axis. To accomplish these objectives, studies are proposed using methods established in the applicants' laboratory, including cannulation of the rodent cerebroventricular system for delivery of neuropharaceuticals, detailed measurements of food intake and body composition, determination of plasma hormone levels by radioimmunoassay, and quantitation of neuropeptide mRNA levels by in situ hybridization. Fulfilling the objectives of t his application will make an important contribution to our understanding of the fundamental processes that underlie the regulation of body adiposity. Substantial progression the development of effective therapeutic strategies for disorders of body weight across the spectrum ranging from obesity to wasting illness can be anticipated from this new knowledge.